The Center for Biologics Evaluation and Research (the Center) of the Food and Drug Administration (FDA or the Agency) has information indicating that you repeatedly or deliberately failed to comply with the requirements of 21 C.F.R. Part 312 in your capacity as an investigator in clinical trials with an investigational new drug. The violations provide the basis for the withdrawal of your eligibility as a clinical investigator to receive investigational new drugs.

The Center's findings are based on information obtained during FDA's inspection of the following clinical studies in which you are the clinical investigator of record:

Pursuant to section 312.70 of Title 21, Code of Federal Regulations (CFR), the Center informed you, by letter dated August 27, 2008, of the specific matters complained of and offered you an opportunity to respond to them in writing or at an informal conference that same letter gave you the option of entering into a consent agreement with the Agency, thereby terminating any administrative proceeding. You chose to respond in writing in a letter that was dated October 17, 2008. The Center has concluded that your written explanation is unacceptable because it falls to adequately address the violations set forth below.

Accordingly, you are being offered an opportunity for a regulatory hearing pursuant to 21 CFR Part 16 and 312.70, on the question of whether you are entitled to receive investigational new drugs. You have the right to be advised and represented by counsel at all times. Any regulatory hearing on this matter will be governed by the regulations in 21 CFR Part 16 and the agency's guidelines on electronic media coverage of administrative proceedings, 21 CFR Part 10, Subpart C. Enclosed you will find copies of these regulations. A list of the specific violations follows. These are the matters that will be considered at the regulatory hearing. Applicable provisions of the CFR are cited for each violation.

1. You failed to protect the rights, safety, and welfare of the subjects under your care, and you failed to conduct the investigations according to the investigational plan, the signed investigator statement, and applicable regulations, including Part 50. [21 CFR § 321.60].

A. You enrolled 21 indigent persons from a multi-service center for the homeless into either study 009 or 012. Only after enrolling eight of these subjects, you received approval from the Institutional Review Board (IRB) to enroll vulnerable subjects, as described below. Regardless of the IRB's decision to approve the enrollment of vulnerable populations, persons utilizing the multi-service center for the homeless were unsuitable for consideration for these studies for many reasons, including, but not limited to the following:

i. These individuals were unsuitable because they were economically and/or educationally disadvantaged. Some subjects could not understand or follow the protocol requirements. For example, subjects (b)(6) and (b)(6) did not understand how to measure his/her temperature in order to complete his/her daily diary, as they reported body temperatures ranging from 84°F to 97°F.

ii. A multi-service center for the homeless lacks the appropriate environment for proper aseptic care of the vaccination site and the safe handling of contaminated dressings described in the "Instruction for the Subject for Care of the Vaccination Site." Although these instructions directed subjects to return soiled bandages to your clinic for disposal, it is uncertain who was exposed to the soiled dressings before they were disposed of.

For example, the multi-service center provided shower and laundry facilities that were used by many individuals. The instructions state:

Clothing or other cloth materials that have contact with the vaccination site should be laundered in hot water with detergent and bleach, if possible. Please don not handle clothing that has come in contact with vaccine recipient's clothing prior to be laundered.

By including subjects from this location, you created a circumstance which may have exposed service users, center staff, and volunteers to the smallpox virus without any knowledge of their pregnancy, immune status, health status, or age. In addition, subjects at the multi-service center for the homeless could have had close contact with other people with unknown health conditions, which presented an increased risk for the uncontrolled spread of the live smallpox vaccine through direct and indirect contact.

iii. Section 4.1, Inclusion Criteria, in both protocols required that subjects must be available for participation during the entire study, and must agree to comply with all protocol requirements. The subjects recruited at the multi-service center for the homeless were placed at increased risk because you could not ensure that they were available for the required health status assessments after vaccination Although your staff repeatedly attempted to contact these individuals, many subjects were not able to be contacted for required 3- and/or 6- month safety follow-up telephone interviews because they lacked a permanent address and/or phone number. Example include the following:

Subject

Study

(b)(6)

009

(b)(6)

009

(b)(6)

012

(b)(6)

012

(b)(6)

012

(b)(6)

012

(b)(6)

012

(b)(6)

012

(b)(6)

012

(b)(6)

012

iv. The 19 page informed consent document for these studies contains technical and complex medical terminology that an educationally disadvantaged subject would have difficulty in reading and fully comprehending.

In your letter dated October 17, 2008, you stated that you did not agree with the study coordinator (an employee of Discovery Alliance) visiting the multi-service center for the homeless but you do not offer any explanation as to why you ultimately enrolled at least 21 persons from this same center. Your letter does not address the specific violations listed under A.i. through A. iv.

B. the "Smallpox Vaccine Risk Assessment Questionnaire" was to be completed at least six times during the study (during screening, prior to vaccination, and during all follow-up visits). The questionnaire asks about the health and medication use of the subjects' household contacts. Because "household contacts" include every user, staff member, or volunteer at the multi-service center, subjects from the Center could not be expected to provide reliable information about the health conditions and medication of all household contacts. you proposed, and the IRB approved, to have an impartial witness observe the informed consent discussion during recruitment of subjects from the multi-service center for the homeless. However, you did not implement this protocol appropriately because, among other deficiencies, you did not establish criteria for who qualified as an impartial witness.

i. In addition, the use of an impartial witness to add extra protections for vulnerable subjects was compromised: (b)(6) signed as the "impartial witness" on the consent form for Subject (b)(6) when she was also a subject in the study (subject (b)(6), and was, therefore, not "impartial."

ii. The dates on the informed consent form for Subject (b)(6) do not show that the subject's consent was witnessed and the informed consent discussion occurred at the same time. Subject (b)(6) signed the informed consent document on 2/18/04. The person conducting the informed consent discussion did not sign the form until 3/1/04, and the witness did not sign the form until 2/25/04. You signed the form as the clinical investigator on 2/27/04. A handwritten note on the form states "witnessed on 18 Feb 04. Inadvertently [sic] not signed until 25 Feb 04." The subject was vaccinated on 2/25/04.

In your letter dated October 17, 2008, you state that you were not aware of these deficiencies and that "paperwork" "was the responsibility of Discovery Alliance." Your response is inadequate because you did not provide any evidence or written documentation in support of your assertion and, further, as the clinical investigator, you are responsible for the conduct of the investigation.

In your October 17, 2008 letter you did not offer any explanation in response to the above allegations listed under B. i. through B. ii.

C. You enrolled at least two relatives of one of the unblinded vaccinators who had full access to the randomization log. This practice raises concerns about the integrity of the randomization process at your site.

In your letter dated October 17, 2008, you state that you "did not know that this happened" and that you were "lied to by Discovery Alliance." Your response is inadequate because you did not provide any evidence or written documentation in support of your assertion and, further, as the clinical investigator, you are responsible for the conduct of the investigation.

D. You performed screening procedures on several prospective subjects who did not meet the inclusion criteria, such as age and prior smallpox vaccination status. These prospective subjects underwent EKGs, and provided blood and urine samples even through they were obviously ineligible to participate in the studies.

In your letter dated October 17, 2008, you stated that you do not have access to the subjects' charts, and therefore you are unable to comment. You also state that if an order for screening was not done properly, you were not aware of it. This response is inadequate.

E. You failed to promptly inform the IRB of all serious adverse events (SAEs) for the 009 study. Section 5.6.2 of the protocols required each investigator to promptly report all serious and unexpected adverse events to their IRB, and to maintain copies of records that document that the IRB was properly notified. Examples of your failure to follow this requirement include:

i. Subject (b)(6) was referred to a cardiologist for follow-up of an abnormal EKG performed on 2/27/04, study day 10. The subject was later found to have acute myocarditis and was subsequently hospitalized for chest pain. You did not notify the IRB about this serious adverse event until 16 days later, in a letter dated 3/15/04.

ii. Subject (b)(6) was hospitalized for possible peripheral neuropathy, with an onset of 4/1/04, which was later diagnosed as somatic transformation. You did not notify the IRB of this SAE until two and a half months later in a letter dated 6/18/04.

In your letter dated August 2, 2006, responding to the FDA Form 483, you state that you had assigned the reporting of serious adverse events to one of your staff who failed to follow the procedures. while certain research functions may be delegated to staff members, as the clinical investigator, you remain ultimately responsible for all aspects of the clinical research. Due to the suspected risk of cardiac SAEs associated with the study vaccines, it was critical that the IRB be promptly informed of these SAEs.

In your letter dated October 17, 2008, you state that you were the first person involved in this nationwide study to identify someone with myocarditis, and that you personally referred the subject to a cardiologist, and notified the sponsor. You further state that you depended upon Discovery Alliance to notify the local IRB, and you assumed they did so in a timely manner. This response is inadequate because as the clinical investigator, you were ultimately responsible for the prompt notification of the IRB.

F. You did not perform serum pregnancy test on women of childbearing potential as all visits for which testing was required according to the protocol and informed consent.

Subject

Serum pregnancy test not done or results not received

(b)(6)

Day 21 2/19/04

(b)(6)

Day 21 2/20/04

(b)(6)

Day 0 2/20/04

(b)(6)

Day 21 3/15/04

(b)(6)

Day 0 2/27/04

In your letter dated October 17, 2008, you explain that you do not have access to the medical charts and deny any wrongdoing on your part. Your response is inadequate.

G. Critical safety assessments at days 7, 10, 21, and 30 were not conducted by qualified health care professionals. The Site Personnel Log for each study documents that you delegated duties to study personnel who were not medically qualified to perform those tasks. For example, study coordinator (b)(6) who claimed to be a Certified Clinical research Coordinator, conducted assessments of adverse experiences, and determined severity and relationship of the adverse events to the test articles. Under the protocol, these assessments should be performed by physicians, cardiologists and neurologists.

Assessments conducted by JS

Subject

Risk assessment questionnaire

Study visits, measured vital signs, AEs and relationship and severity

(b)(6)

Medical history

(b)(6)

Study visit

(b)(6)

Study visit

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Medical history

(b)(6)

Study visit

(b)(6)

Screening history

(b)(6)

Screening history

(b)(6)

Risk assessment questionnaire

(b)(6)

In your letter dated October 17, 2008, you explain that you do not have access to the medical charts and deny any wrongdoing on your part. Your response is inadequate.

H. You did not review the results of screening laboratory tests for subject (b)(6) until after the subject was vaccinated. The results were reported on 2/28/04, the subject was vaccinated on 3/2/04, but you did not review the results until 3/5/04.

In your letter dated October 17, 2008, you explain that you do not have access to the medical charts and deny any wrongdoing on your part. Your response is inadequate.

I. You did not perform the cardiac physical exam and test for CPMB or follow the required cardiac algorithm for subject (b)(6) who was found to have cardiac related abnormalities on day 10. You did not review the troponin lab result from day 10, which was March 12, 2004, until May 4, 2004, after the active phase of the study. Furthermore, you did not review the lab reports for day 21 as documented on the case report form.

In your letter dated October 17, 2008, you explain that you do not have access to the medical charts and deny any wrongdoing on your part. Your response is inadequate.

J. You did not obtain vital signs for the following subjects as required by the protocols:

Subject

Days vital signs not measured

(b)(6)

Day 10

(b)(6)

Days 7, 10, and 21

(b)(6)

Days 0, 7, 10, 21, 30

(b)(6)

Days 7 and 21

(b)(6)

Days 0, 7, 10, and 21

(b)(6)

Days 10 and 21

(b)(6)

Day 30

(b)(6)

Day 10

(b)(6)

Days 0, 7, 10, and 21

(b)(6)

Days 0, 7, 10, and 21

In your letter dated October 17, 2008, you explain that you do not have access to the medical charts and deny any wrongdoing on your part. Your response is inadequate.

2. You made changes in the research without IRB approval and failed to promptly report all changes in the studies. [21 CFR § 312.66]

You began the practice of recruiting vulnerable subjects from the multi-service center for the homeless before you received IRB approval to do so. On 2/24/04 you requested approval to include economically or educationally disadvantaged people as a potential source for subject recruitment. You had already enrolled three vulnerable subjects by this date, and had screened others. The IRB approved your request on March 2, 2004, but your site did not receive the notification and the approved consent form revision until March 8, 2004, by which time you had enrolled at least eight subjects. In the application for IRB review the IRB specifically asked if you intended to enroll individuals from a list of 20 vulnerable populations, which includes: homeless persons, unemployed or impoverished persons, ethnic minority groups, mentally ill, limited or non-readers, or others that may be vulnerable to coercion. You checked the box "No."

In your letter dated August 2, 2006, in response to the FDA Form 483, you state that once you realized that your study staff was recruiting and enrolling subjects from a multi-service center for the homeless, you requested that the IRB review and approve additional safeguards, consisting of a revised informed consent form that added a signature line for and impartial witness.

In your letter dated October 17, 2008, you state that you have already addressed this concern [under item 1, above]. The matter you refer to having already addressed (items 1A i. to iv.) concerns the unsuitability of subjects being enrolled into the studies rather than enrolled vulnerable subjects prior to receiving IRB approval to do so. Your response is inadequate because you failed to provide a sufficient explanation for not seeking IRB approval before enrolling these subjects.

3. You failed to maintain adequate and accurate case histories, including all observations and other data pertinent to the investigation. [21 CFR § 312.62(b)].

You signed case report pages for subjects' visits days before the visits actually occurred. For example, subject (b)(6) was seen on 2/27/04 (Day 10). You signed forms for this visit in at least four places, in which you dated your signature as 2/18/04, 2/20/04, 2/25/04, or 2/26/04.

In your letter dated October 17, 2008, you state that you never signed a form for work before it was done but do not provide evidence or written documentation to support your assertion. You previously stated that you do not have access to the case histories to explain this allegation.

Your request for a hearing must be made, in writing, within ten (10) business days of receipt of this letter and should be directed to Eugene Leger, Acting Director, Division of Compliance Management and Operation, Office of Enforcement, Office of Regulatory Affairs, Telephone 240-632-6868, Fax 240-632-6859. If no response to this letter is received by the time, you will be deemed to have waived any right to a regulatory hearing, and a decision in this matter will be made based on the facts available to the agency. No hearing will be held.

A request for a hearing may not rest upon mere allegations or denials but must present specific facts showing that there is a genuine and substantial issue of fact that warrants a hearing. Pursuant to 21 CFR 16.26, a request for a hearing may be denied, in whole or in part, if the Commissioner or his delegate determines that no genuine and substantial issue of fact had been raised by the material submitted. A hearing will not be granted on issues of policy or law or unsubstantiated questions of fact. Written notice of a determination of summary judgment will be provided, explaining the reasons for denial of the hearing.

If you wish to respond but do not desire a hearing, you should contact Eugene Leger within the time period specified above and send a written response containing your reply. The letter should state that you waive your right to a hearing and that you want a decision on the matter to be based on your written response and other information available to the agency.

The agency's offer to enter into a consent agreement attached to the Notice of Initiation of Disqualification Proceedings and Opportunity to Explain letter dated August 27, 2008 remains available. Entering into a consent agreement would terminate the administrative procedures, but would not preclude the possibility of a corollary judicial proceeding.

No final decision by FDA has been made at this time on your eligibility to continue to use investigational new drugs. Moreover, there will be no prejudgment of this matter if you decline to enter into a consent agreement and decide instead either to request a regulatory hearing or to request that the decision be based on information currently available to the agency.

Please inform Eugene Leger within ten (10) business days of whether you wish to request a hearing or to have this matter resolved by consent agreement or information available to the agency.